July 29, 2013

Updated policy brief: Future directions in hepatitis C treatment - closing in on a cure for the vast majority

Professor Gregory Dore

July 2013

Policy Brief 1

Key Messages

Hepatitis C is a viral infection that is curable with pegylated interferon and ribavirin (PEG-IFN/RBV) in around 60% of people, but has considerable side effects and requires relatively prolonged treatment duration (24-48 weeks).

When combined with PEG-IFN/RBV in triple therapy regimens these initial DAA agents improve cure rates (by 20-25%), and shorten treatment duration from 48 to 24 weeks for around half of patients.

Although increasing cure rates, there are several concerns with these initial two DAA agents: not effective against genotype 2/3; additional toxicity (e.g. rash, anaemia); problematic dosing (three times per day with food); and complex monitoring schedules and stopping rules.

Several other DAA agents in development appear to be as potent (and possibly more potent), have reduced toxicity, and better dosing schedules (some are once daily), and should become available in 3-4 years.

Several studies of combination DAA treatment (without PEG-IFN/RBV) have been extremely encouraging in demonstrating cure of hepatitis C in 90%. The first available IFN-free DAA regimen is likely to be sofosbuvir (Nucleotide analogue) and ribavirin with a treatment cure (called a sustained virological response - SVR) of 90% for genotype 2 and 60% for genotype 3.

The future of hepatitis C treatment with DAA therapy is extremely promising - with the potential to cure the vast majority of people commenced on therapy. The challenge now and into the future is to increase access to treatment as currently only one to two per cent of Australians with chronic hepatitis C commence treatment each year.

As people who inject drugs are the group at greatest risk of hepatitis C, further research and specifically developed treatment programs will be crucial.

What is the issue?

Hepatitis C is somewhat unusual among chronic diseases generally and chronic liver disease specifically – it is eminently curable. Around 60% of people commenced on current standard of care (PEG-IFN/RBV) will be cured of their chronic hepatitis C infection, with most people also having reversal of underlying liver damage. However, current treatment remains problematic due to the considerable side effects, the requirement for contraception during and for six months following treatment (due to RBV causing foetal malformation), the relatively prolonged treatment duration (24-48 weeks), and the restrictive settings in which most treatment is provided (tertiary clinics in large hospitals). As such, only 1-2% of people with chronic hepatitis C are commenced on treatment each year in Australia.

The landscape of hepatitis C treatment will alter enormously over the coming decade following the development of direct acting antiviral (DAA) agents that enhance treatment efficacy (that is more people will be cured of their hepatitis C). The duration of therapy will be shortened with treatment demonstrated to be curative without interferon-based therapy. As new treatments become available, there will be a need to evaluate them among current injecting drug users, the group at greatest risk of hepatitis C infection who have to date been excluded from clinical trials developing these agents. It will also be crucial to improve access through specifically developed treatment programs.

What is the evidence?

Over the last 12 months several major milestones have been reached in the clinical development of DAA therapy for chronic HCV infection. The initial HCV protease inhibitors, telaprevir and boceprevir, have been approved in Australia for use in combination with PEG-IFN/RBV for people with HCV genotype 1 who have never previously been treated for hepatitis C (treatment naïve) and people previously treated for hepatitis C (treatment experienced).

In treatment naïve populations, telaprevir or boceprevir when added to PEG-IFN/RBV improved the chance of a treatment cure (called a sustained virological response - SVR) from 40-45% to 65-75% and enabled the length of treatment to be shortened from 48 weeks to 24-28 weeks for around half of patients. In treatment experienced populations, telaprevir and boceprevir both provided considerably enhanced but variable SVR when combined with PEG-IFN/RBV (from 30% to 85%).

Although telaprevir and boceprevir are now listed on the Pharmaceutical Benefits Scheme, several concerns remain regarding these two agents, including:

Problematic dosing schedule of three times per day with a meal (fatty for telaprevir), and large pill burden (boceprevir, 12 pills per day; telaprevir, 6 pills per day);

Low level of treatment response (efficacy) in patients who had a minimal reduction in the level of the virus when treated with PEG-IFN/RBV in the past, particularly those with advanced fibrosis (15-20% SVR);

The potential for drug resistance;

Increased side effects – in particular rash (telapravir) and anaemia (bocepravir and telapravir);

Potential for a large number of drug interactions due to the way that telapravir and bocepravir are broken down in the liver (they impact on the cytochrome P450 (CYP) 3A4 pathways);

The strategies for administering telapravir and bocepravir in particular vary (they have different “start” and “stop” rules) and can be confusing for both patients and doctors.

Telaprevir and boceprevir are only approved for HCV genotype 1.

There are several important pathways for future DAA clinical development, with many studies recently releasing promising findings. Some of the major areas for development will include:

IFN-free DAA regimens: There are several promising regimens in development. Sofosbuvir and ribavirin should be licensed by the US Food and Drug Administration in late 2013 for HCV genotype 2 (12 weeks) and HCV genotype 3 (16 weeks), based on SVR rates of around 90% for genotype 2 and 60% for genotype 3. Subsequent regimens will combine at least 2 DAA agents, possibly without the need for ribavirin, and possibly with activity against all HCV genotypes.

Over the next five to ten years there will be major improvements in hepatitis C therapy, with simplified, short duration, probably once daily single combination pill dosing. Side effects and pill-burden (the number of tablets the person needs to take each day) will also reduce.

Preliminary evidence that IFN-free regimens are curative and the development of other promising once-daily agents shines a bright light on the way forward.

The Treatment Action Group in New York produces excellent community-based reports on hepatitis C treatment developments in their Pipeline Report series. See the chapter titled ‘Hepatitis C drug development goes from pony ride to rocket launch’ by Swan and Kaplan in the most recent report - HIV, Hepatitis C Virus (HCV), and Tuberculosis (TB) Drugs, Diagnostics, Vaccines, and Preventive Technologies in Development(Clayden et al. 2012) Go to the website for Pipeline Reports and updates

The natural history of hepatitis C virus infection differs between women and men. Women demonstrate a slow rate of disease progression until menopause. Older women are more likely to develop fibrosis and are less responsive than younger women to pegylated interferon and ribavirin. Women of childbearing age have higher rates of sustained virologic response, but current therapies are contraindicated during pregnancy. Vertical transmission of hepatitis C virus occurs, but data supporting recommendations for prevention of mother-to-infant transmission are limited.

Introduction

Approximately 3 million people in the United States are chronically infected with the hepatitis C virus (HCV),[1] which is transmitted primarily through contact with the blood of an infected person. Acute infection resolves in approximately 20% of cases and the rest develop chronic infection.[2] The major sequelae of chronic HCV infection are cirrhosis and hepatocellular carcinoma.[2] The clinical course varies widely among individuals, with sex influencing the natural history and clinical outcomes. Understanding the unique features in women will assist clinicians in managing female patients with chronic HCV infection.

Prevalence and Natural History of HCV in Women

Since the implementation of blood product screening, injection drug use (IDU) has become the most common mode of HCV acquisition.[1] Sex does not affect the risk of acquiring HCV. Although women in the United States historically have demonstrated a lower prevalence of HCV infection,[3] their sex likely reflected their lower rate of IDU[4] because sex differences in HCV prevalence are not seen in other cultures.[5] In addition, a meta-analysis of 30 studies reported that female prison inmates are 40% more likely than are male prison inmates to be infected with HCV.[6] Female injection drug users also exhibit higher rates of HCV infection than their male counterparts,[7,8] a difference that is related to behavior rather than biology: Female injection drug users frequently share injection equipment and engage in unsafe sex practices,[7,9] including having intercourse with people with whom they also inject drugs.[10,11]

Although sex does not appear to affect the risk of HCV infection, it does influence its outcome. A systematic review of 31 longitudinal studies found that 40% of women versus 19% of men will resolve acute HCV infection.[12] Genome-wide association studies have reported that genetic variation surrounding the interleukin-28B (IL-28B) locus is associated with enhanced response to interferon-based therapies and spontaneous resolution of HCV infection.[13] A cohort study of Danish injection drug users noted that women with favorable IL-28B genotypes were six times as likely as women with unfavorable genotypes to spontaneously clear HCV infection;[14] however, even when controlling for the IL-28B genotype, women remain more likely than men to spontaneously clear HCV infection.[15]

Women also manifest slower progression to two major chronic HCV infection complications, cirrhosis and hepatocellular carcinoma. In a cohort of 376 Irish women chronically infected with HCV from contaminated anti-D immunoglobulin, only 1.9% had progressed to histological cirrhosis after a mean of 17 years following exposure.[16] The low rate of fibrosis progression was confirmed in a 25-year follow-up study of 167 women, of whom 1.2% developed histological cirrhosis.[17] Male sex was identified as an independent risk factor for developing hepatocellular carcinoma in several studies.[18,19] This sex-specific predilection for complications of liver disease is not completely understood. Some experts posit that higher estrogen states exert a protective effect on the liver.[20] Animal models suggest that estrogen suppresses hepatic fibrosis,[21–23] and a recent in vitro study proposed that estrogen inhibits the production of HCV virions.[24] Multiparous women exhibit lower stages of fibrosis than nulliparous women, and fibrosis progression accelerates after menopause.[25,26] In observational studies, women who received hormone therapy (HT) appeared to have a slower progression to fibrosis;[20] however, the benefits of HT in women with HCV have not been established. HT appears to be safe in women with liver disease when indicated for other reasons.[20]

Modifiable Risks for Progression of Liver Disease

Excessive alcohol intake accelerates the progression to HCV-related cirrhosis. Studies demonstrate consumption of >30 g/day increases the risk for cirrhosis in hepatitis C threefold.[27] Current guidelines stress the importance of abstinence from alcohol for all patients with HCV.[28] Accumulating evidence suggests that women infected with HCV are more vulnerable than their male counterparts to the effects of alcohol.[20] A prospective study illustrated that women who consumed >20 g/day doubled their risk for increased fibrosis, whereas men required >30 g/day to reach a similar risk increment.[29] Healthcare providers should encourage women with chronic HCV to abstain from alcohol or, alternatively, to limit intake to an equivalent of 12 g/day of ethanol.

Increased body mass index (BMI) also appears to accelerate disease progression, regardless of sex. Multiple studies have illustrated an increased risk for progression of liver disease in patients who are overweight (BMI ≥ 25 kg/m2) or obese (BMI ≥ 30 kg/m2).[30–32] In a small prospective study of patients with chronic hepatitis C, a mean body weight reduction of 5.9 (±3) kg resulted in lower alanine aminotransferase levels and reduced levels of fibrosis on liver biopsy;[33] thus, even modest weight loss may reduce the risk of the progression of liver disease.

Effect of Sex and Age on Treatment Response

The primary goal of treatment of HCV is the prevention of cirrhosis and hepatocellular carcinoma by eradicating the virus. The surrogate marker for viral eradication is a sustained virologic response (SVR), defined as an undetectable serum HCV viral load 6 months after completing therapy. Studies of hepatic C therapeutics that examined SVR rates by sex reported conflicting findings. Overall, men and women appear to have equal responses to pegylated interferon and ribavirin.[34,35] When stratified by age, however, SVR rates for women dramatically decline with older age, a phenomenon that has not been observed in men[36–38] (). Similar to their protective effects on the progression of liver disease, higher estrogen states are hypothesized to promote SVR.[37] Studies of telaprevir or boceprevir in combination with pegylated interferon and ribavirin illustrate equivalent response rates among men and women with genotype 1 HCV[39–42] (). These studies did not further stratify women by age, although in some studies older age was associated with overall lower rates of SVR.[35,43]

Table 1. Studies that stratified sustained virologic response to interferon-based therapies by sex and age

Study

Women

P

Men

P

Age group, y

SVR, %

Age group, y

SVR, %

Hayashi et al36

<40

75

<0.0001

<40

33

<0.001

≥40

16

≥40

25

Sezaki et al37

<50

71

0.03

<50

69

0.41

≥50

32

≥50

63

Villa et al38

Premenopausal

68

<0.0001

<45

59

0.114

Postmenopausal

46

≥55

50

SVR, sustained virologic response.

Table 2. Summary of SVR rates by sex for phase III studies examining the addition of telaprevir or boceprevir to pegylated interferon and ribavirin

Women with advanced liver disease are at increased risk for complications during pregnancy, but the effects of maternal HCV infection on natal outcomes are less well defined.[44] Recent evidence suggests that HCV infection may increase the risks for gestational diabetes, low birth weight, and neonatal intensive care unit admission.[45,46] Modifiable risk factors, such as IDU and limited prenatal care, may be more prevalent in patients with HCV,[41] which could confound data on maternal and fetal outcomes.

Pregnancy may improve the natural course of HCV infection. In the second and third trimesters, alanine aminotransferase levels decrease, whereas serum levels of HCV RNA increase.[47] This could imply that decreased hepatocyte damage, possibly related to increased estrogen levels and/or placental interferon production, occurs during pregnancy. Although alanine aminotransferase and HCV RNA serum concentrations return to prepregnancy levels within several months of delivery, women with multiple gestations do exhibit slower disease progression.[21]

Vertical transmission is the major cause of HCV infection in children.[45] Maternal–infant transmission occurs in roughly 5% of cases in which the mother is infected with HCV,[48] but recommendations regarding prevention are limited by insufficient high-quality data. The timing of transmission also is poorly understood; evidence exists for both in utero and transvaginal transmission.[49] Frequently identified risk factors for vertical transmission are high maternal HCV viral load and human immunodeficiency virus (HIV) co-infection.[50,51] Prolonged rupture of membranes (>6 hours) has been associated with more frequent perinatal transmission.[50] In addition, some experts recommend avoiding invasive procedures that promote fetal exposure to maternal blood, such as fetal scalp monitoring.[50,52] Elective cesarean section has been proposed to reduce the risk of vertical transmission;[53] however, this practice is not recommended for women infected with HCV unless they are co-infected with HIV.[52] Some studies have reported that because an elevated serum viral load increases the risk of transmission,[50,51] women who achieve remission from HCV before conception may reduce their risk of transmitting the virus to their fetuses.

Although HCV RNA has been detected in breast milk and colostrum,[54] breast-feeding does not appear to be a primary route of maternal–infant HCV transmission.[50,55] Some experts believe that the quantity of virions in these bodily fluids is insufficient to result in infection and that gastric acid exerts a protective effect.[52] Mothers infected with HCV are encouraged to breast-feed in the absence of other contraindications, such as HIV-1 co-infection, but they should be counseled that there is limited study on this topic.[56] The Centers for Disease Control and Prevention propose temporary interruption of breast-feeding when the mother has cracked, bleeding, or traumatized nipples, which could increase exposure of the infant to HCV.[57]

Antiviral Therapy in Women

Choosing when to initiate HCV therapy in women can be challenging, particularly with regard to maternal age and family planning. There is evidence that advanced age decreases the likelihood of an SVR in women more so than in men.[29,30] Given the risk of vertical transmission, it may be preferable to complete treatment in women of reproductive age before they conceive. Because use of ribavirin is contraindicated in pregnancy, women of childbearing age who are considering therapy for HCV require careful counseling regarding the potential danger to a child conceived during the treatment period.

Although ribavirin has not been studied formally in human gestation, several animal studies have demonstrated significant embryocidal and teratogenic effects; as a result, ribavirin is contraindicated during pregnancy (pregnancy category X).[58] The serum half-life of ribavirin is 12 days; the drug also is pooled in erythrocyte populations, which can result in prolonged postadministration exposure.[59] Two forms of effective contraception are required during and 6 months following therapy with ribavirin in women capable of conception.[58] Women who are capable of conception should be aware that if their male partners are receiving ribavirin, then the use of two forms of contraception during and 6 months after treatment is recommended. In addition, women of childbearing age should take a pregnancy test before treatment initiation and submit to monthly pregnancy tests during the treatment period.[58] Because ribavirin has not been studied in human pregnancy, women inadvertently exposed to ribavirin 6 months before or during pregnancy should consider enrollment in the Ribavirin Pregnancy Registry (www.ribavirinpregnancyregistry.com).

The effects of interferon on the fetus are uncertain (pregnancy category C). Interferon-[alpha] does not appear to cross the placental barrier or demonstrate teratogenic effects.[60] Case studies of pregnant women with leukemia have not demonstrated fetal malformation associated with interferon use, but intrauterine growth retardation has been observed in this setting.[61]

Boceprevir and telaprevir have been assigned to pregnancy category B by the Food and Drug Administration; however, these medications are administered exclusively with ribavirin and pegylated interferon-[alpha], precluding any use during pregnancy. Both drugs are potent CYP3A4 substrates and inhibitors, resulting in many potentially dangerous interactions with other drugs, including oral contraceptives. Telaprevir and boceprevir may cause systemic hormonal contraceptives to be unreliable during concurrent administration.[62,63] Drosperinone concentrations double in the presence of boceprevir, contraindicating coadministration because of concern for potentiating hyperkalemia.[63] Barrier methods and intrauterine devices are the preferred methods of contraception in women receiving boceprevir or telaprevir in combination with pegylated interferon-[alpha] and ribavirin.[55,56] Given the wide range of drug–drug interactions involving these agents, close review of package inserts or consultation with a clinical pharmacist is recommended in patients receiving concomitant medications during therapy.[64]

Conclusions

The natural history of HCV infection differs between women and men. Women are more likely than men to clear acute HCV infection. With chronic HCV infection, women experience a slower progression to cirrhosis and are less likely than men to develop hepatocellular carcinoma. Accelerated disease progression occurs in postmenopausal women; older women also have lower rates than younger women of SVR to pegylated interferon and ribavirin. Infected women of childbearing age should be educated about the risks of perinatal HCV transmission and the potential teratogenicity of current treatment regimens. All women with HCV should be counseled on the effects of alcohol and obesity on the progression of liver disease.

Sidebar

Key Points

In the absence of comorbid conditions, women with hepatitis C virus (HCV) infection experience a slower progression to cirrhosis and a lower risk of hepatocellular carcinoma.

Following menopause, the incidence of liver damage increases and women become less responsive to interferon-based therapies for chronic HCV infection.

Abstinence from alcohol and maintenance of a healthy weight reduce the risk of liver disease progression in patients with chronic HCV.

Achieving a sustained virologic response before conception may reduce substantially the risk of vertical HCV transmission; however, current therapies carry risks of fetal malformation.

Fertile women who receive pegylated interferon and ribavirin should be counseled to use two forms of contraception. Because of drug–drug interactions with estrogen-based oral contraceptives, this form of birth control is unreliable in women receiving telaprevir or boceprevir.

Between 40,000 and 80,000 Austrians suffer from hepatitis C. With new infections the prompt and appropriate treatment is of great importance as this can prevent it developing into a chronic illness which in turn can progress to inoperable liver cancer. Now a research team led by scientists of the MedUni Vienna has succeeded in developing a points system enabling a better prognosis as to whether the illness will become chronic or whether the acute hepatitis C will spontaneously heal itself.

"This is significant by virtue of the fact that, for patients with a tendency towards developing a chronic illness, early treatment with antiviral medication affords a better chance of healing," explains hepatologist Harald Hofer of the University Department of Internal Medicine III at the MedUni Vienna, Clinical Department of Gastroenterology and Hepatology (Chief: Michael Trauner).

The points system was developed by the MedUni Vienna researchers from a combination of clinical and biochemical parameters. Says Hofer: "Using this, the clinical course of the acute hepatitis C can be much better predicted, which means that the costly antiviral therapy with its many side effects can be much more efficiently deployed." The results of the study have been now published in the leading Journal of Hepatology.

Towards an interferon-free therapy

The advances made in treating hepatitis are generally remarkable. Two new, direct acting antiviral substances (DAA/"Direct Acting Antiviral Therapy") have been submitted for licensing not only in Europe but also in the USA (Simeprevir and Sofosbuvir), and will, according to Hofer, also be available in the foreseeable future. "For some of the patients this means that interferon-free therapy is becoming a reality outside clinical trials as well."

Current standard treatment is a combination therapy with interferon-alpha, which possesses an immune-stimulating, antiviral effect. In cases of hepatitis C interferon is injected once a week over a period of up to twelve months – although with undesirable side effects such as aching limbs, fever, headaches, as well as depressive episodes or malfunctions of the thyroid. The advantage of direct antiviral therapy (DAA) is that it acts directly on the hepatitis C virus and is thus more effective – with fewer side effects.

People in detention are particularly vulnerable to Hepatitis B and C. On World Hepatitis Day, we should consider what can be done to prevent the spread of these diseases.

Hepatitis B and C are diseases that, if left untreated, can kill. It is estimated by the World Health Organisation that, worldwide, over 2 billion people have been infected by Hepatitis B and 150 million people chronically infected with Hepatitis C. Both diseases are thought to cause between 500,000 to 700,000 deaths a year globally.

Every country in sub-Saharan Africa considers viral hepatitis a serious public health issue but, due to a lack of data, its impact is not accurately known. What we do know is that the prevalence rate for Hepatitis B is estimated at 8% in West Africa and 5-7% in Central, Eastern and Southern Africa. The rate for the more virulent Hepatitis C is even higher and may be as much as 10%.

One of the groups most vulnerable to Hepatitis B and C, as well as HIV, are those held in detention. Both Hepatitis B and C may be spread through exposure to blood, especially during unsafe practices such as sharing injecting equipment and tattooing, as well as through unprotected sexual relations.

To respond to HIV in prisons, the UN Office on Drugs and Crime and other UN organisations have developed a comprehensive package of 15 key interventions that includes the vaccination, diagnosis and treatment of viral hepatitis. All of these interventions are essential, but I would suggest five other ways we can further enhance their effectiveness.

Five recommendations

First, of the 30 million people held annually in detention globally, most leave within a few months or a year and return to their communities. For this reason, let's tear down the concept of "prison walls" when it comes to Hepatitis B and C, and in doing so, acknowledge that prisoners may return home with a communicable disease. Good prison health is an essential element of public health.

Second, people living in prisons must have access to medical treatment and prevention measures to stop the spread of diseases like Hepatitis B and C. Access to health is guaranteed by international law.

Detainees must receive the same healthcare opportunities as those offered in the wider community. For the sake of public health, and for everyone's human rights, we cannot afford different health standards for different social groups.

Third, the issue of gender must be addressed. Women experience detention differently to men and have a higher vulnerability to sexual violence and abuse. The services offered in prison should be tailored to their needs and concerns. Let's also do the same for other groups in detention such as injecting drug users, those living with HIV, and young people.

Fourth, overcrowding, violence, the absence of protection from the climate, poor lighting and ventilation are all associated with detention in some parts of the world. When these conditions are combined with poor diets, low access to clean drinking water, and inadequate personal hygiene, they exacerbate health problems in detention.

Fifth, prison should be the final and not the first option for a range of defendants. Pre-trial detainees comprise one third of all those held in detention and many are accused of lesser crimes. Safe, community-based alternatives to pre-trial detention can help stem the spread of disease and relieve overcrowded detention centres.

Every one of our efforts to increase access to health should also be connected to wider reforms addressing living and working conditions in prisons. The above is not an exhaustive list, but on World Hepatitis Day it marks a move in the right direction.

So much of our work is rightly based on protection; however, we must also accept that, in some areas, potential barriers to success exist. Our duty is to tear down these barriers. Health is far too important to leave these walls standing.

Yury Fedotov is the Executive Director at the United Nations Office on Drugs and Crime.

The frequent use of injections can add to the risk of Hepatitis infection. IRIN/Kamila Hyat

28 July 2013 – Marking World Hepatitis Day, the head of the United Nations drugs and crime agency today called for stronger prevention efforts to stop the spread of this major global health risk and urged authorities to ensure that all victims, including injecting drug users and prisoners, get the care and treatment they need.

“All people suffering from viral hepatitis deserve access to the same level of care and treatment available in the community,” the Executive Director of UN Office on Drugs and Crime (UNODC), Yury Fedotov, said in his message for the Day.

“If interventions are to be effective, they must be grounded in respect for the human rights and right to health of all sufferers,” Mr. Fedotov added.

Hepatitis is an inflammation of the liver, most commonly caused by a viral infection. There are five main hepatitis viruses, referred to as types A, B, C, D and E, which lead to 1.4 million deaths every year.

Hepatitis C can lead to liver diseases such as cirrhosis and cancer, and infection is widespread among injecting drug users. According to UNODC's 2013 World Drug Report, global prevalence of hepatitis C among people who inject drugs is estimated at 51 per cent.

Among the prison populations, hepatitis infection is also many, many times higher than in the general population, UNODC said, noting that a majority of people detained will return to their communities, some within months.

“Many of those infected with hepatitis are unaware, and therefore may go undiagnosed and untreated, posing a risk of transmission to their families, coworkers and neighbours,” Mr. Fedotov noted.

UNODC and its UN partners promote an integrated response to preventing hepatitis and providing treatment and care, the senior UN official said. This includes comprehensive packages of interventions for injecting drug users and prisoners to stop the spread of HIV and other infectious diseases such as hepatitis B and C.

Necessary measures include treating drug dependency and instituting condom programmes, as well as needle and syringe programmes.

The UN World Health Organization (WHO) is currently developing new hepatitis C screening, care and treatment guidelines, which will provide recommendations on seven key areas such as testing approaches; behavioural interventions (alcohol reduction); non-invasive assessment of liver fibrosis; and the selection of hepatitis C drug combinations.

The World Health Assembly – the decision-making body of WHO – designated 28 July as World Hepatitis Day. The Day serves to promote greater understanding of hepatitis as a global public health problem and to stimulate the strengthening of preventive and control measures against infection in countries throughout the world.

Coinciding with this year's marking of the Day, WHO released its first-ever country hepatitis survey. Covering 126 countries, the 'Global policy report on the prevention and control of viral hepatitis in WHO member States' identifies successes as well as gaps at country level in the implementation of four priority areas: raising awareness, evidence-based data for action, prevention of transmission, and screening, care and treatment.

The findings show that only one-third of the world's countries have national strategies for viral hepatitis, leading WHO to urge Governments to scale up measures to tackle the spread of the disease.

Program Officer, International Harm Reduction Development Program and Access to Essential Medicines Initiative, Open Society Foundations

Posted: 07/29/2013 2:08 pm

The World Health Organization has dubbed hepatitis C, which infects as many as 185 million people worldwide, a "viral time bomb." On this World Hepatitis Day, July 28, it is important to know that this "bomb" can be defused if we can get companies to lower the price of treatment.

Unlike cancer or HIV, hepatitis C is curable in the majority of cases. Unfortunately, cure has been hampered by the fact that the bulk of people living with hepatitis C reside in low- and middle-income countries where the main medicine used in the current standard of care -- Pegylated Interferon-alfa (Peg-IFN) -- is priced out of reach. Two pharmaceutical giants -- Roche and Merck -- sell all of the brand-name Peg-IFN around the world. This duopoly allows the companies to charge exorbitant prices. Even in countries where patients have to pay for treatment out of their own pockets, the cost of hepatitis C treatment can be as high as $18,000 USD for a course of treatment. For too many, this is a price tag that means death.

We know these medicines need not be so expensive. As the table below shows, these companies agree to sell the same medicines at vastly different prices from country to country, with no apparent logic. And, it is widely known that the costs of manufacturing represent only a fraction of this high price tag, with the remainder, often over 90 percent, being profit.

In some countries, breakthroughs in price reduction have been made. In Egypt, for example, where there is a large hepatitis C epidemic, and a locally-produced competitor to the brand-name medicines, the government was able to secure treatment made by Merck and Roche at less than $2,000 for a 48-week course of treatment. The drop in price allowed the government to treat approximately 220,000 people under its national program.

And, in Thailand, the government was able to commit to cover hepatitis C treatment under its universal health care program after negotiating a four-fold reduction in price for Peg-IFN by Roche and Merck to $4,800 USD for a 48-week course of treatment.

Inspired by the examples of Egypt and Thailand, governments and activists in other low- and middle-income countries, like Georgia and Ukraine, are starting to ask for reduced prices to effectively address their national epidemics. To mark World Hepatitis Day this year, activists protested the high price of hepatitis C treatment at rallies in Russia, Armenia, Georgia, Ukraine, and Latvia. And in Asia, groups are preparing to ask Merck and Roche to drop the price to $1,000 USD a year.

We know that political commitment and community mobilization can make the difference. For those who say that treatment is too complicated or that pharmaceutical companies will always prioritize profit over people, we should say: we've been here before. More than a decade ago, HIV/AIDS patients marched the streets ofSouth Africa, Thailand, and Brazil demanding affordable access to medicines that could save their lives, and with success. Since then, the cost of AIDS drugs dropped from over $10,000 per person per year to less than $100 today, enabling millions to access treatment.

So, this World Hepatitis Day, we stand in solidarity with civil society groups in low- and middle-income countries, and their governments as they mobilize in the fight for access to hepatitis C treatment. Affordable access to life-saving medicines is a human right, and only when governments and pharmaceutical companies commit to making treatment available at fair prices, will we close the hepatitis C treatment gap. If these companies continue to put profits before people, the hepatitis C epidemic will surge, and many more will unnecessarily die.

Follow the Open Society Foundations' Public Health Program on Twitter: @OSFHealth

A rift between board members who organize the largest annual HIV/AIDS meeting in North America has led to its heavily used website going dark in early July and confusion about where the conference will take place in 2014.

The 20-year-old Conference on Retroviruses and Opportunistic Infections (CROI) attracts up to 4000 researchers from around the world, and its website—a rich archive of abstracts, webcasts, and podcasts—has become a go-to spot for researchers, community advocates, historians, and journalists. The nonprofit CROI Foundation and the for-profit CROI LLC put the meeting on, and the dispute involves a falling-out between the two groups. “I’m not allowed by our confidentially agreement to divulge anything,” says CROI Foundation Board President Constance Benson, an HIV/AIDS researcher at the University of California, San Diego (UCSD). “We reached an impasse this past couple of years over several issues and decided we needed to go in a different direction.”

CROI LLC is run by Melissa Sordyl, a co-founder of the meeting and conference secretariat, who also sat on the board of directors of the CROI Foundation with a high-powered group of HIV/AIDS researchers. Sordyl says that the foundation terminated their agreement. “They have not made any effort to reach out,” she says. “They only talk through lawyers.” She says that CROI LLC owns the website and took it down at the beginning of this month simply because they no longer have an agreement with the foundation.

Benson’s husband, UCSD HIV/AIDS clinician and researcher Robert Schooley, launched CROI with Sordyl after the U.S. government began to restrict travel of its scientists to international conferences in the early 1990s. Several groundbreaking discoveries have been announced at the meeting over the years, including the success of combinations of antiviral drugs, the origins of HIV, and the cure of Timothy Brown. According to CROI Foundation tax reports to the Internal Revenue Service in 2010, it has become a big business, with nearly $8.9 million in net assets. (It’s unclear from the tax reports how much CROI LLC received in payment for its services.)

HIV/AIDS advocates in particular have lobbied the CROI Foundation to resurrect the website quickly. “CROI is established as the most important HIV scientific meeting, and their commitment to the website is unparalleled in the medical field and should be a model for other disease areas,” wrote Simon Collins, co-founder of the U.K.-based HIV treatment information website i-Base, in an e-mail to others in the advocacy community. “The website is a vital resource not only as a record of previous meetings, but as a free, open-access research tool. i-Base, along with many other community organisations, goes to considerable effort to include hyperlinks to abstracts, posters, presentations and webcasts in our reports. The reliability of the original URLs are an essential aspects of the site. The lack of communication is not helpful.”

Benson says that the CROI Foundation has formed a partnership with the International Antiviral Society-USA, a nonprofit headquartered in San Francisco, California, that will serve as the new secretariat and organize the meeting. Benson says they will announce later today that the meeting will be held on 3 to 6 March in Boston. As for the website, Benson says that they want to relaunch it as soon as possible, but it’s unclear how much of the archive material, which CROI LLC owns, will appear. “We’re going forward with putting whatever content we have on the new website,” Benson says. “We are in discussion about what can be done to reestablish materials on the previous website.”

Recognizing the rapid development of hepatitis C medications coupled with increasing numbers of people being identified with hepatitis C virus (HCV) infection, the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) are collaborating to develop clinical recommendations for the management of hepatitis C.

New medications approved by the Food and Drug Administration in recent years have increased HCV cure rates, and several additional medications are expected to be approved in the next three to five years. At the same time, new HCV testing guidelines are expected to increase the number of patients diagnosed with hepatitis C, many of whom currently are HCV-infected but unaware of their status. Ensuring that patients receive the new, effective treatment will be critical in increasing cure rates for hepatitis C. "We can finally say that cure of HCV infection has become a real possibility for the majority of individuals infected with this deadly virus," said Gary Davis, MD, of AASLD.

"Members of AASLD and IDSA are committed to ensuring that patient care keeps pace with rapidly advancing science," said David Relman, MD, president of IDSA. "This effort is an important step toward advancing that goal and comes at an important time as we all work to raise awareness of hepatitis virus infections on World Hepatitis Day on July 28."

Through this collaboration, the societies will review current treatment recommendations and use evidence-based, consensus guidance to develop updated recommendations for managing patients. Recommendations will be updated regularly and made available online. "A web-based system of new recommendations coupled with a published annual update will afford the greatest opportunity for both rapid and comprehensive output," said Donald M. Jensen, MD, of AASLD.

About Hepatitis C

Hepatitis C is a liver disease resulting from chronic infection with the hepatitis C virus (HCV). It is estimated that between 3 million and 4 million Americans are infected with HCV and have chronic liver disease as a result. Because symptoms of HCV infection may not appear for many years, more than 70 percent are unaware they are infected.

Earlier this year, the Centers for Disease Control and Prevention recommended an age-based screening strategy consisting of a one-time test for HCV for those at highest risk, including everyone born between 1945 and 1965. This recommendation was endorsed by the U.S. Preventive Services Task Force in June 2013. The broader testing recommendations likely will detect a substantial number of people who are unaware they are infected.

According to a July 10, 2013 article published in The Journal of The American Medical Association (JAMA), deaths from liver disease increased from 1990 to 2010. HCV is the most likely cause of the emergence of liver disease as a growing threat to Americans. Early testing enables people who are infected to receive treatment as soon as possible, and prevent progression to more serious disease, such as cirrhosis and liver cancer.

Currently available drugs and the next generation of direct-acting antivirals that will likely be available later this year offer the potential to treat and cure most patients with HCV infection. Therefore, up-to-date recommendations for the medical management of these patients and their treatment are critically important.

About the AASLD

AASLD is a medical subspecialty society representing clinicians and researchers in liver disease. The work of our members has laid the foundation for the development of drugs used to treat patients with viral hepatitis. Access to care and support of liver disease research are at the center of AASLD’s advocacy efforts.

AASLD is the leading organization of scientists and healthcare professionals committed to preventing and curing liver disease. AASLD was founded in 1950 by a small group of leading liver specialists and has grown to an international society responsible for all aspects of hepatology.

Press releases and additional information about AASLD are available online at www.aasld.org.

About IDSA

The Infectious Diseases Society of America (IDSA) is an organization of physicians, scientists, and other health care professionals dedicated to promoting health through excellence in infectious diseases research, education, prevention, and patient care. The Society, which has nearly 10,000 members, was founded in 1963 and is based in Arlington, VA. For more information, see www.idsociety.org.

GlaxoSmithKline (GSK) has received a positive opinion from the European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) recommending marketing authorisation for Revolade(eltrombopag) as a treatment for low platelet counts (thrombocytopenia) in adult patients with chronic hepatitis C infection, where the degree of thrombocytopenia is the main factor preventing the initiation or limiting the ability to maintain optimal interferon-based therapy.

“A sustained virologic response is the goal for treatment of hepatitis C infection and our clinical study, the largest ever in cirrhotic patients with low platelet counts and chronic hepatitis C infection, demonstrated that eltrombopag in combination with interferon-based therapy, allowed more cirrhotic patients with low platelet counts to reach this goal,” said Dr Rafael Amado, head of Oncology R&D, GlaxoSmithKline. “We’re looking forward to working with the regulators to attain full marketing authorisation for this indication.”

The CHMP opinion is based on review of safety and efficacy data for eltrombopag, including two randomised, double-blind, placebo controlled, multi-centre phase III studies of more than 1500 patients. A CHMP positive opinion is one of the final steps before marketing authorisation is granted by the European Commission, but does not always result in marketing authorisation. Hepatitis C virus (HCV) infection is the most common blood borne viral infection, and is associated with chronic liver disease which can lead to a number of blood-related disorders including low platelet count (thrombocytopenia). Treatment with pegylated interferon and ribavirin is the current standard of care for patients with HCV, however both the European Association for the Study of the Liver guidelines and the American Association for the Study of Liver Diseases report the presence of thrombocytopenia among the relative contraindications to antiviral therapy.

In the European Union (EU), eltrombopag is currently approved as a treatment for thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenia (ITP). In the US, eltrombopag is marketed under the trade name PROMACTA and is currently approved as a treatment for patients with chronic immune (idiopathic) thrombocytopenia who have had insufficient response to corticosteroids, immunoglobulins, or splenectomy and as a treatment for thrombocytopenia in patients with chronic hepatitis C infection to allow the initiation and maintenance of interferon-based therapy.

The most important serious adverse reactions identified in the ITP or HCV trials were hepatotoxicity, including hepatic decompensation events and thrombotic/ thromboembolic events.

GlaxoSmithKline is committed to improving the quality of human life by enabling people to do more, feel better and live longer.

(CNN) -- Here's a look at what you need to know about AIDS and HIV globally, with a special focus on Africa.

Facts:AIDS stands for acquired immunodeficiency syndrome, and is also called acquired immune deficiency syndrome.

HIV stands for human immunodeficiency virus.

HIV/AIDS is spread through sexual contact with an infected person, sharing needles with an infected person, through transfusions of infected blood or through an infected mother.

People infected with HIV go through three stages of infection: 1) Acute infection, or acute retroviral syndrome, which can produce flu-like symptoms in the first month after infection. 2) Clinical latency, or asymptomatic HIV infection, in which HIV reproduces at lower levels. 3) AIDS, in which the amount of CD4 cells fall below 200 cells per cubic millimeter of blood (as opposed to the normal level of 500-1,500).

HIV-1 and HIV-2 can both cause AIDS. HIV-1 is the most common human immunodeficiency virus; HIV-2 is found mostly in western Africa.

Historical Timeline:1981 - CDC publishes reports of men in Los Angeles, New York and San Francisco who were previously healthy and are suffering from rare forms of cancer and pneumonia, and accompanied by "opportunistic infections."

1982 - Disease adopts the name AIDS.

1983 - French and American researchers determine that the HIV virus is caused by AIDS.

1985 - Blood tests to detect HIV are developed.

December 1, 1988 - First World AIDS Day.

1999 - Researchers in the U.S. find evidence that HIV-1 most likely originated in a population of chimpanzees in West Africa. The virus appears to have been transmitted to people who hunted, butchered and consumed the chimpanzees for food.

2011 - The UN announces that the overall number of new HIV infections has decreased by 20 percent in the past decade.

2011 - The use of antiretroviral drugs has increased the life expectancy of those with HIV/AIDS.

June 5, 2011 - The 30th anniversary of the first five reported CDC cases of AIDS.

October 2011 - In his book The Origins of AIDS, Dr. Jacques Pepin traces the emergence and subsequent development of HIV/AIDS to suggest that initial AIDS outbreaks began earlier than previously believed.

March 3, 2013 - Researchers announce that a baby born infected with HIV has been "functionally cured." The child, born in Mississippi, was given high doses of antiretroviral drugs within 30 hours of being born. Two years later, doctors were unable to detect evidence of HIV in the child's blood.

The U.S. President's Emergency Plan for AIDS Relief (PEPFAR):January 29, 2003 - In his State of the Union speech, President Bush promises to dramatically increase funding to fight HIV/AIDS in Africa.

July 30, 2008 - H.R. 5501, The Tom Lantos and Henry J. Hyde United States Global Leadership Against HIV/AIDS, Tuberculosis, and Malaria Reauthorization Act of 2008, becomes law and authorizes up to $48 billion to combat global HIV/AIDS, tuberculosis and malaria. Through 2013, PEPFAR plans to work in partnership with host nations to support treatment for at least 4 million people, prevention of 12 million new infections, and care for 12 million people.

September 30, 2012 - PEPFAR has supported life-saving antiretroviral treatment for approximately 5.1 million men, women and children since 2003.

July 2012 - PEPFAR announces its latest results. The program is supporting 4.5 million people on treatment and has donated more than $7.1 billion to the Global Fund to Fight HIV/AIDS, Tuberculosis and Malaria.

July 24, 2012 - Doctors announce during the 19th International AIDS Conference that Timothy Ray Brown, the Berlin patient, has been "cured" of HIV. Brown, diagnosed with leukemia, underwent a bone marrow transplant in 2007 using marrow from a donor with an HIV-resistant mutation. He no longer has detectable HIV.

2013 - Under PEPFAR, the U.S. Government has committed approximately $46 billion to HIV/AIDS programs, the Global Fund to Fight HIV/AIDS, Tuberculosis and Malaria, and tuberculosis programs through 2010.

June 18, 2013 - Marking the 10th anniversary of PEPFAR, Secretary Kerry announces that the millionth child has been born HIV-free due to prevention of mother-to-child transmission programs (PMTCT).

2013 - President Obama's PEPFAR budget request for 2014 fiscal year includes $6 billion for global aids prevention, $1.65 billion for the Global Fund to Fight HIV/AIDS, Tuberculosis and Malaria, and $1.1 billion for the Department of Veterans Affairs.

The Yomiuri Shimbun Anticancer drugs are likely to be more effective against prostate cancer, which is resistant to such drugs, if they are administered with medicine used to treat hepatitis C, according to recent research using mice.

A joint research team of Keio University and the National Institute of Advanced Industrial Science and Technology (AIST) announced the finding in the online version of the Japanese Cancer Association’s journal. The discovery is expected to contribute to the development of treatment for highly malignant forms of cancer.

The team, led by Keio University Prof. Toshio Suda, focused on Oct4, a gene known for its association with prostate cancer that is highly resistant to drug treatment. Isolating high-grade cancer cells strongly influenced by Oct4, the team examined genes related to malignant transformations and compared them to ordinary cancer cells.

Using a database of the effects on cancer cell genes of about 1,300 candidate substances for medicine, the team discovered nine candidate substances that could help suppress genes that play a role in the formation of malignant tumors.

The team administered one of the candidates, Ribavirin, which is used to treat hepatatis C, along with an anticancer drug to six mice that had high-grade prostate cancer transplanted onto their backs. Although the cancerous cells grew from 150 cubic centimeters to 190 cubic centimeters, their growth was smaller than that for mice that were administered only anticancer drugs. The cancer grew to 300 cubic millimeters in one of the latter cases.

Disclosure: I have no positions in any stocks mentioned, and no plans to initiate any positions within the next 72 hours. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.

What happened: Amid the positive biotech earnings on Thursday, Vertex (VRTX) announced after the close that the FDA had put the US Phase 2 study of VRTX's hepatitis C [HCV] drug VX-135 on partial clinical hold. This clinical hold halts the evaluation of the 200mg dose group but allows treatment with the 100mg VX-135 dose, in combination with ribavirin, to continue in the US study. The reason given for the regulatory caution was because the FDA learned the 400mg VX-135 dose with ribavirin led to elevated liver enzymes in a separate European Phase 2 study.

Dosing of 100 mg and 200 mg of VX-135 in combination with ribavirin as part of a 12-week Phase 2 study in Europe is complete, and all patients are in the post-treatment follow-up period. Ten patients with genotype 1 hepatitis C were enrolled in each dose group and all 20 patients completed 12 weeks of treatment. Both the 100 mg and 200 mg doses were well tolerated, no serious adverse events have been reported and no liver or cardiac safety issues have been identified. All patients achieved undetectable HCV RNA during the 12-week dosing period, and 70 percent and 80 percent of patients in the 100 mg and 200 mg dosing arms, respectively, had undetectable HCV RNA within four weeks of initiating treatment. HCV RNA was undetectable at the end of the treatment period in all patients with available data. Complete safety and efficacy results from the 100 and 200 mg arms of the study are expected to be available in the second half of 2013. Following completion of enrollment in the 100 mg and 200 mg arms of the European study, the study was amended to evaluate a 400 mg dose of VX-135 in combination with ribavirin in ten patients. Elevated liver enzymes were observed in three of ten patients in this dose group, including one serious adverse event, and the 400 mg arm of the study was discontinued. Following the discontinuation of dosing, liver enzyme levels returned to baseline in all three patients.

What you needed to know before this:

HCV is the part of the VRTX pipeline that I'd argue is still relatively unappreciated (the other big part being cystic fibrosis, of course). However, sellside analysts and investors have been growing increasingly excited about the upside potential of VX-135 (aka ALS2200, which was exclusively licensed from Alios), which has been in Phase 2 studies. Like cystic fibrosis, HCV is undeniably a blockbuster market. VX-135, like Gilead's (GILD) GS7977 (aka sofosbuvir/PSI-7977), belongs to the exciting, but controversial new drug class in HCV treatment of nucleoside analogs or "nucs." The nucs can arrest DNA replication and therefore help prevent the virus from multiplying. Basically, the nuc class has demonstrated the potential to become the dominant backbone of a next-generation all-oral HCV regimen (briefly, they have shown potency, unprecedented cure rates beyond conventional treatments, a relatively high barrier to developing viral resistance, and tolerability). Certainly, this is the potential future GILD seems to be envisioning for 7977. And not only is VX-135 also a nuc but it is also of the uridine type (one out of the four possible DNA nucleotide bases) like GILD's 7977. However, where the controversy lies, the clinical and regulatory hurdle VX-135 must clear, is safety. Several nucs (BMS094/INX189, PSI-938, IDX184) have been put on clinical hold by the FDA for safety concerns, presumably including heart failure and liver enzyme elevations. Of the clinical stage nucs, only GILD's and VRTX's drugs were left standing after the FDA's previously raised concerns. On the 1Q earnings call, VRTX management guided to the first 12-week safety data for VX-135 being available from roughly 40-60 patients by year-end. Many institutional investors have seen this dataset as critical to derisk the safety profile of VX-135, albeit a larger dataset of >100 patients would likely be needed to make the decision to take the drug into pivotal trials.

My $.02:

Given the prior FDA stance, Thursday's news raises serious questions about the future of the VX-135 program and the HCV pipeline. Elevated liver enzymes can be clinically irrelevant or they can be potentially concerning, if indicative of drug-induced liver injury. Appropriately, the FDA is not taking any chances on that possibility. On a positive note, I would pick a liver enzyme elevation over a known cardiac issue to contend with any day and the fact there is a partial clinical hold, not a full hold, allows other studies and doses to continue to accumulate safety data. Even so, questions remain whether VX-135 is likely to continue development and if it does, whether this safety issue would effectively cripple the commercial competitiveness of VX-135 or the ability to combine/partner VX-135 with other HCV assets. Without VX-135, the hopes of building a competitive all-oral HCV regimen would likely evaporate. Then, VRTX would end up with no HCV franchise at all, since most professional investors assume that sales of Incivek (the marketed HCV protease inhibitor) will basically go away once far superior HCV regimens become available in 2014.

VRTX is one of those biotech companies that have delivered plenty of controversy in the last couple of years, whether it's from the competition weighing against its lead drugs or, more recently, from an ill-timed stock sale by management. However, until today, it seemed to be doing well recently (stock rallied from $50s into low $80s) on the heels of positive data developments in its cystic fibrosis (CF) pipeline, leading VRTX to emerge as the dominant player in the CF space. (As a reminder, cystic fibrosis is a genetic disease where mutations in a gene lead to thick mucus. This clogs the airways and predisposes to infections and worse life expectancy.) With Kalydeco already in the CF market and a handful of other complementary assets to combine with, VRTX has the potential to target a substantial portion of the CF mutations (I estimate $6-7B in sales potential).

However, prior to today, my long thesis on VRTX has been that with potentially two strong blockbuster franchises in CF and HCV, VRTX would have flexibility in determining its next leg of revenue growth. Without VX-135, the story erodes significantly and VRTX would become more dependent on success in CF and the rest of the pipeline (e.g., VX-509 for rheumatoid arthritis), which is far less exciting to me.

The trade:

For fundamental investors, I mention the aftermarket selloff (~$6-7 off) of VRTX seems appropriate to me to reflect removing the risk-adjusted value of VX-135 from the VRTX valuation (which for me is based on a sum-of-the parts). Without VX-135, my upside valuation of VRTX loses $20-30/share from removing the full value of an all-oral HCV combo regimen. Before this, I would have argued the risk-reward of VRTX becomes less favorable around $90-ish/share. Now, I would argue the risk-reward becomes less attractive once the stock gets into the low $80s. On the other hand, the scarcity value of GILD's 7977 just went up as it's the only clinical-stage nuc left with a clear regulatory path.

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